Infants of diabetic mothers (IDM) are often born with hypertrophic cardiomyopathy. Regulation of remodeling of the newborn IDM heart and the long-term consequences of the neonatal cardiac hypertrophy are not well defined. The objectives of this proposal are to define the mechanisms that contribute to cardiac hypertrophy in the IDM, elucidate the signaling pathways that regulate postnatal normalization of cardiac mass, and identify the long-term sequelae. The specific aims that will be studied include: 1) Demonstrate that increased cardiac mass in the IDM heart is due to both hypertrophy and hyperplasia and that postnatal remodeling results in fewer, larger myocytes;2) Verify that resolution of the IDM cardiomyopathy is due to activation of apoptosis regulated by the mitogen-activated protein (MAP) kinase signaling pathways;and 3) Demonstrate that adult hearts of IDM have greater susceptibility to an ischemia/reperfusion insult. We have developed a rat model of gestational diabetes that results in macrosomic rat pups with a hypertrophic cardiomyopathy. Using this model, morphometric studies of postnatal IDM hearts and isolated myocytes will be performed to address Aim 1. Aim 2 will be approached by administration of specific inhibitors of the MAP kinase signaling pathways to IDM and control rat pups. Activation of apoptosis will be assessed while remodeling of the heart will be evaluated by echocardiography and morphometric measurements. Both in vivo coronary ligation and isolated, perfused heart studies will be used to determine susceptibility to ischemic injury in the adult hearts of animals born to diabetic dams (Aim 3). The long-term objective of these studies is to understand the remodeling that takes place in the neonatal heart such that rationale strategies can be identified to enhance adaptive, and suppress maladaptive, changes in the hypertrophied IDM heart. The goal of these interventions will be to improve cardiac function later in life. The results from these studies should be applicable to other forms of congenital heart disease that are associated with ventricular hypertrophy and postnatal remodeling of the ventricles. Public Health Relevance: The obesity epidemic in the U.S. is accompanied by a greater number of diabetics and an increase in gestational diabetes. Significant hypertrophy of the newborn heart, which occurs in 30- 40% of infants of diabetic mothers, limits neonatal cardiac function and leads to long-term abnormalities of the cardiovascular system. Results from this proposal will define the mechanisms by which the IDM heart remodels after birth and develops long-term dysfunction, ultimately allowing interventions to be identified to protect both developing and mature hearts.